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Identification of the neural circuits involved in Attention Deficit Hyperactivity Disorder

par Pozuelo Fernandez, Elisa
Président du jury Langer, Ingrid
Promoteur Schiffmann, Serge N.
Co-Promoteur de Kerchove d'Exaerde, Alban
Publication Non publié, 2019-09-10

Thèse de doctorat

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Résumé :

Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental psychiatric disorder affecting 5-7% of children and ≈2.5% of adults worldwide, characterized by inattention, by a combination of hyperactivity and impulsivity, or by the three components. Individuals diagnosed with ADHD have an increased risk of educational and occupational failure, accidents, criminality, social disability and developing other psychiatric disorders, being an important burden for the patient and for society.Despite years of research, the etiology of ADHD remains unknown. However, neuroimaging studies demonstrated that ADHD patients display consistent abnormalities in the striatum, the main input nucleus of the basal ganglia, while the precise implication is poorly characterized. The most common pharmacological treatment in ADHD relies on psychostimulants such as amphetamine (Adderall) and methylphenidate (Ritalin). Importantly, in healthy individuals, these drugs stimulate behavioral arousal by increasing the brain efflux of monoamines, while they paradoxically serve to attenuate hyperactivity/impulsivity and improve focus and cognitive performances in ADHD patients. The goals of this thesis are to investigate the implication of one striatal neuronal population in ADHD symptomatology in a transgenic mouse line and to dissect the implication of each monoaminergic system in the paradoxical effects of psychostimulants. First, we developed a new valid mouse model of ADHD characterized by hyperactivity, inattention and motor impulsivity, that displays an ablation of the indirect pathway spiny projection neurons (iSPNs) of the striatum. In addition, in these mice, amphetamine induces a paradoxical reduction of locomotion, which mirrors the calming effect of amphetamine in ADHD patients. In this work, we thus show for the first time the implication of iSPN in attention and impulsivity and suggest a possible role of these neurons in ADHD symptomatology. Further, by using a chemogenetic approach, we identified the dopaminergic system as the monoaminergic system preferentially involved in the paradoxical effects of amphetamine in this model. Moreover, by optogenetic manipulation of dopaminergic neurons in the ventral tegmental area, we found that only a tonic photostimulation pattern mimics the amphetamine-induced reduction of locomotion, indicating a firing mode specificity in this effect. In conclusion, with this thesis, we contributed to the understanding of ADHD etiology and the mechanism involved in amphetamine treatment.